Boosting Antipsychotic Drugs

While antipsychotic drugs the symptoms of many people with schizophrenia, around a third of patients resist such treatments. A new study, led by Javier Gonzalez-Maeso of the Mount Sinai School of Medicine, suggests that this frustrating intractability depends on how DNA is packaged.

Gonzalez-Maeso and his colleagues found that antipsychotic drugs can suppress the expression of glutamate receptors in the brain, stunting their effectiveness as treatments for schizophrenia. But the researchers also found a way of boosting the effects of antipsychotics—by pairing them with drugs that block the gene suppression pathway. They published their results today (August 5) in Nature Neuroscience.

The finding “represents another important avenue of scientific enquiry in our efforts to enhance the therapeutic response in schizophrenia,” said Peter Buckley, a psychiatrist at Georgia Health Science University who was not involved in the research.

Second-generation antipsychotic drugs target the receptors for two brain signaling chemicals—dopamine and serotonin. In 2008, Gonzalez-Maseo established showed that serotonin and glutamate receptors interact antagonistically, with serotonin receptors linked to psychotic behaviors, and glutamate receptors linked to suppression of those symptoms. “These receptors do opposite things,” he said. “The signaling pathways that are activated by one are blocked by the other.”

Now, the team has shown that long-term doses of antipsychotics suppress both pathways in a mouse’s frontal cortex—an area of the brain involved in thought and perception. Thus, while the drugs may reduce psychotic episodes caused by the overactivation of serotonin receptors, they also hinder the helpful effects of the glutamate ones.

The reason for this, it turns out, is because the drugs change the structure of DNA in a way that inhibits the expression of mGlu2, the glutamate receptor gene. The genome’s long strands of DNA wrap around proteins called histones to fit neatly inside the cell nucleus. Mount Sinai’s Mitsumasa Kurita used antibodies that recognise different types of histone modifications and found that clozapine, a second-generation antipsychotic drug, can alter the histones near a mouse’s mGlu2 gene after just 3 weeks of treatment. The drug increases the levels of an enzyme called HDAC2, which alters the histones ahead of mGlu2 so they pack DNA more tightly. This silences the gene, and prevents glutamate receptors from being made.

The result is worse psychotic symptoms. When Kurita loaded mouse brains with extra copies of HDAC2, the rodents produced fewer glutamate receptors and developed more schizophrenia-like behaviors, such as head twitches, hyperactivity, and poorer performance on memory tasks.

But by injecting the rodents with SAHA, a drug that inhibits HDAC2, the researchers were able to reverse these effects. Glutamate receptor levels went up and behavioral tics fell away. SAHA even boosted the antipsychotic effects of clozapine. For example, clozapine on its own slashed the frequency of head twitches in the mice by two thirds, but the addition of SAHA cut that frequency even further.

Gonzalez-Maseo hopes that these results will encourage other scientists to develop drugs that block HDAC2 as ways of treating schizophrenia, in conjunction with antipsychotics. But, as psychiatrist Herbert Meltzer of Northwestern University Feinberg School of Medicine points out, HDAC inhibitors have not improved the effects of antipsychotics in clinical trials. “Indeed, virtually all the evidence is to the contrary,” said Meltzer, noting that the HDAC inhibitor valproate has been tested with very mixed results. “Unless future studies provide more support for this strategy, it is not possible to urge scarce research dollars to be spent on the search for other HDAC2 inhibitors for this indication.”

Gonzalez-Maseo counters that valproate is a very broad-ranging inhibitor, and he hopes that drugs which target HDAC2 more specifically will show stronger effects. Indeed, drugs that target mGlu2 receptors directly have already shown some promise in clinical trials as ways of controlling psychotic symptoms.